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ASSESSING NEW CFDA REQUIREMENTS ON DATA INTEGRITY

USING RISK-BASED MONITORING AND ENROLLMENT PATTERNS

WENJUN BAO, RICHARD ZINK AND GEOFFREY MANN JMP LIFE SCIENCES , SAS INSTITUTE INC.

PHUSE

OCT. 2017

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OUTLINES

Ø CFDA Announcements: Ø Assess and Ensure Quality

Ø Efficient Approaches Ø RBM Ø Enrollment Pattern

Ø Conclusions

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July 22, 2015

Dec. 17, 2015

April 1, 2016

June 3, 2016

CFDA ANNOUNCEMENTS: ENSURE QUALITY

May 19, 2017

Sept. 13, 2017

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DATA SELF-EXAM AND AUDIT

临床研究大汇 CFDA8/12/2015

Efficacy

Safety: AE and SAE

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DATA SELF-EXAM AND AUDIT

临床研究大汇CFDA 8/12/2015

Enrollment Speed

Screen Success Rate

Discontinued Rate # Enrollment

Leader’s Site

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DATA SELF-EXAM AND AUDIT

SELF-EXAM & AUDIT

Safety Enrollment Participation

AE, SAE, Death

Screen Fail Discontinued

Speed Subject Number

RBM

Efficacy Site Leader

DRUG

SITE

Enrollment Pattern

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RISK-BASED MONITORING RBM

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Oct. 2017: http://www.transceleratebiopharmainc.com/about/meet-the-members/

Members of Transcelerate BioPharma Inc.

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RISK-BASED MONITORING (RBM)

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TRADITIONAL VS RISK-BASED MONITORING

Ø  Expensive[1-3]

25~ 30% Trial Cost Ø  Local data Ø  Human Capacity[3]

v  Efficiency and accuracy

v  data trends across time, patients, and clinical sites [4, 5]

v  95% identified from database [6]

1.EisensteinELetal(2005).AmericanHeartJournal149:482–488.2.FunningSetal(2009).TheQualityAssuranceJournal12:3-7.3.TantsyuraVetal(2010).DrugInforma9onJournal44:745-756.

4.TransCelerateBioPharmaInc.(2013).hKp://transceleratebiopharmainc.com/5.ZinkRC.(2014).ISBN-13:978-1612909912,.Cary,NC:SASInsUtute.6.BakobakiJMetal.(2012).ClinicalTrials9:257-264.

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VARIABLES

RISK-BASED MONITORING (RBM)

Risk Indicators

Safety Data Quality

Recruitment & Discontinuation

Staffing, Facilities & Supplies Essential

Documents

Risk threshold

CDISC Domain

AE (Adverse Event) DM (Demographics)

DS (Disposition) SV (Subject Visits)

EX (Exposure) DV (Protocol Deviations)

IE (Inclusion/Exclusion Criterion Not Met)

ADSL

RULES

Risk Evaluation

Maps

Traffic-light system

Distributions

RESULTS 1Position Paper: Risk-Based Monitoring Methodology. TransCelerate Biopharma Inc, 2013 2Risk-Based Monitoring and fraud detection in clinical trials using JMP and SAS. Richard Zink 2014

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RISK-BASED MONITORING (RBM) I. RISK THRESHOLD SETUP

Risk Indicators

Safety Data Quality

Recruitment & Discontinuation

Staffing, Facilities & Supplies Essential

Documents

Risk threshold

RULES 1Position Paper: Risk-Based Monitoring Methodology. TransCelerate Biopharma Inc, 2013 2Risk-Based Monitoring and fraud detection in clinical trials using JMP and SAS. Richard Zink 2014

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VARIABLES

RISK-BASED MONITORING (RBM) II. CDISC DOMAIN FOR INFO

CDISC Domain

AE (Adverse Event) DM (Demographics)

DS (Disposition) SV (Subject Visits)

EX (Exposure) DV (Protocol Deviations)

IE (Inclusion/Exclusion Criterion Not Met)

ADSL

1Position Paper: Risk-Based Monitoring Methodology. TransCelerate Biopharma Inc, 2013 2Risk-Based Monitoring and fraud detection in clinical trials using JMP and SAS. Richard Zink 2014

14

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CDISC:ClinicalDataInterchangeStandardsConsor5um

CDISC SDTM

ADaM

SEND

SE: Subject Elements

Findings Class

Interventions Class

CO: Comments

SV: Subject Visits

AE: Adverse Events MH: Medical History

DS: Disposition

DV: Protocol Deviations

EG: ECG; LB: Lab QS: Questionnaires

VS: Vital Signs

PE: Physical Exams

PC/PP: PK Conc/Parameters

CM: Concomitant Medications

EX: Exposures SU: Substance Use

TA: Trial Arm

TI: Trial In/Exclude Criteria

ADSL

•  ADaM: the Analysis Data Model o  ADSL: the subject-level analysis dataset o  BDS: Basic Data Structure

•  SDTM: the Study Data Tabulation Model •  SEND: the Standard for Exchange of Nonclinical Data

BDS

DM: Demographic

CE: Clinical Events

MB: Microbiology Specimen

IE: In/Exclusion Criterion Not Met

DA: Drug Accountability SC: Subject Characteristics

MS: Microbiology Susceptibility

Events Class

Special Purpose Domain

Trial Design Domain

TV: Trial Visit TE: Trial Elements TS: Trial Summary

Findings About FA: Finding About

Relationship Datasets

Supplemental Qualifiers RELREC: Related Records

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RISK-BASED MONITORING (RBM) III. RESULTS DISPLAY

Risk Evaluation

Maps

Traffic-light system

Distributions

RESULTS 1Position Paper: Risk-Based Monitoring Methodology. TransCelerate Biopharma Inc, 2013 2Risk-Based Monitoring and fraud detection in clinical trials using JMP and SAS. Richard Zink 2014

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RISK BASED MONITORING (RBM)

AE

SAE

Discontinued

Screen

SAFETY

PARTICIPATION

Self-check and Audit for the sites related to RBM: a.  Sites with more AE and/or SAE b.  Sites with more discontinued subjects c.  Sites with more screen fail

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RBM: AE AT COUNTRY LEVEL

不良反应 AES PER PATIENTWEEK

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RBM: SAE AT SITE LEVEL

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RBM: ACTION SUGGESTION BY RISK INDICATORS

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RBM: ACTION SUGGESTION BY RISK INDICATORS

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REAL TIME RBM

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REAL TIME RBM

22

Early Snapshot

Final Snapshot

Snapshots in CDASH

Snapshots in SDTM

JMP Clinical

EDC

Compare Snapshots

D

Clinical D

ata Collection

Mapping Studies

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TWO SNAPSHOT EXAMPLES

Early Snapshot

Final Snapshot

Trial Year 1987 1987, 1988, 1989 Subjects 43 902 Sites 10 40 Countries 1 10

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ADD SNAPSHOTS AS TWO STUDIES

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ADD SNAPSHOTS AS TWO STUDIES

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REAL TIME RBM AEs per PatientWeek

Early Snapshot

Final Snapshot

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REAL TIME RBM SAEs per PatientWeek

Early Snapshot

Final Snapshot

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REAL TIME RBM Death per PatientWeek

Early Snapshot

Final Snapshot

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RISK-BASED MONITORING

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ENROLLMENT PATTERN

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ENROLLMENT ENROLLMENT SPEED AND NUMBER OF SUBJECTS

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ENROLLMENT COMPARISON OF TREATMENT AND PLACEBO GROUPS

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ENROLLMENT COUNTS SUBJECTS BY STUDY DAY

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ENROLLMENT RANDOMIZATION FOR EACH SITE

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CENTRALIZED STATISTICAL MONITORING FRAUD AND PROBLEM DETECTION

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DATA INTEGRITY ANALYSIS

36

Data Integrity

Across Sites

A site vs

others

Within Subjects

Across Subjects

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DATA INTEGRITY Sites Subjects

Across Sites

A Site and/or A Site vs Others

•  Risk-Based Monitoring •  Enrollment •  Birthday and Initial •  Cluster subjects across study sites •  Multivariate Inliers and Outliers

•  Correlated Findings •  Digit Preference •  Frequencies •  Missing Value •  Outliers •  Perfect Scheduled Attendance •  Screen Bias •  Weekend and Holidays

•  Birthday and Initial •  Cluster subjects Within study sites •  Duplicate Records

Within a Site between Subjects

Subject Records

•  Constant Finding •  Duplicate Record •  Multivariate Inliers and Outliers •  Visit Orders

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Ø  CFDA new requirements can use RBM and Enrollment pattern to assess.

Ø  More centralized statistical monitoring Methods are available to further assess the data quality.

CONCLUSIONS

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Powerful Analytics

Visual Interactive

JMP Clinical: Combination of SAS & JMP

Ø Base SAS Ø SAS/STAT Ø SAS/GRAPH Ø SAS/IML Ø SAS/Secure Ø SAS/Secure Windows Ø SAS/Genetics Ø SAS/ACCESS PC Files Ø SAS/IML Studio

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Wenjun Bao, Ph.D. wenjun.bao@jmp.com